An urgent need exists to prevent the sexual transmission of HIV-1 to women. Although infection rates exceed 35% in parts of sub-Saharan Africa, very little attention is devoted to the role of the female reproductive tract (FRT) in preventing viral transmission. This proposal presents an innovative intervention strategy for preventing the acquisition of HIV infection through the lower FRT. Our approach would replenish the body's own anti-HIV molecules during the time of the menstrual cycle (the window of vulnerability) when levels of these molecules are depressed in the lower FRT and when HIV infection would be most likely to occur. This proposal brings together three innovative concepts which are as follows: 1, The Window of Vulnerability concept integrates the biology of the lower FRT with the recent finding that molecules (Elafin, SLPI, HDB2/3, MIP3alpha, etc.) of the innate immune system have significant anti-HIV activity. Our recent findings suggest that normal hormone signaling during the menstrual cycle results in a major depression of the secretion of these molecules in the lower FRT. We hypothesize that because of this depression in the levels of anti-HIV molecules during this window, women are more susceptible to HIV infection, 2, that delivery of sufficient quantities of these anti-HIV molecules to the lower FRT during this window of vulnerability will counter the normal suppression of innate immunity and protect women against HIV infection, and 3, that these molecules can be delivered by commensal bacteria engineered to secrete these molecules in response to the increase in estrogen that occurs during the window of vulnerability. Although the use of commensal bacteria have been used previously to produce various artificial molecules the uniqueness of this proposal is that it combines the three novel concepts outlined above, into a comprehensive and innovative approach that integrates the biology of the lower FRT with the use of naturally occurring delivery system that works in synchrony with the normal hormone cycle. An urgent need exists to prevent the sexual transmission of HIV-1 to women. Although infection rates exceed 35% in parts of sub-Saharan Africa, very little attention is devoted to the role of the female reproductive tract (FRT) in preventing viral transmission. The object of this research is to develop a Lactobacillus delivery system that will replenish the body's own anti-HIV molecules during the time of the menstrual cycle (the window of vulnerability) when levels of these molecules are depressed in the lower FRT and when HIV infection would be most likely to occur.